Lupus patients are in need of modern drugs to treat specific manifestations of their disease effectively and safely. In the past half century, only one new treatment has been approved by the US Food ...and Drug Administration (FDA) for systemic lupus erythematosus (SLE). In 2014–2015, the FDA approved 71 new drugs, only one of which targeted a rheumatic disease and none of which was approved for use in SLE. Repositioning/repurposing drugs approved for other diseases using multiple approaches is one possible means to find new treatment options for lupus patients. “Big Data” analysis approaches this challenge from an unbiased standpoint whereas literature mining and crowd sourcing for candidates assessed by the CoLTs (Combined Lupus Treatment Scoring) system provide a hypothesis-based approach to rank potential therapeutic candidates for possible clinical application. Both approaches mitigate risk since the candidates assessed have largely been extensively tested in clinical trials for other indications. The usefulness of a multi-pronged approach to drug repositioning in lupus is highlighted by orthogonal confirmation of hypothesis-based drug repositioning predictions by “Big Data” analysis of differentially expressed genes from lupus patient samples. The goal is to identify novel therapies that have the potential to affect disease processes specifically. Involvement of SLE patients and the scientists that study this disease in thinking about new drugs that may be effective in lupus though crowd-sourcing sites such as LRxL-STAT (www.linkedin.com/in/lrxlstat) is important in stimulating the momentum needed to test these novel drug targets for efficacy in lupus rapidly in small, proof-of-concept trials conducted by LuCIN, the Lupus Clinical Investigators Network (www.linkedin.com/in/lucinstat).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
An efficient system for genetic modification and large-scale cloning of cattle is of importance for agriculture, biotechnology, and human medicine. Here, actively dividing fetal fibroblasts were ...genetically modified with a marker gene, a clonal line was selected, and the cells were fused to enucleated mature oocytes. Out of 28 embryos transferred to 11 recipient cows, three healthy, identical, transgenic calves were generated. Furthermore, the life-span of near senescent fibroblasts could be extended by nuclear transfer, as indicated by population doublings in fibroblast lines derived from a 40-day-old fetal clone. With the ability to extend the life-span of these primary cultured cells, this system would be useful for inducing complex genetic modifications in cattle
Two standard commercial flashlamp-pumped Nd:YAG lasers have been upgraded to "pulse-burst" capability. Each laser produces a burst of up to fifteen 2 J Q-switched pulses (1064 nm) at repetition rates ...1–12.5 kHz. Variable pulse-width drive (0.15–0.39 ms) of the flashlamps is accomplished by IGBT (insulated gate bipolar transistor) switching of electrolytic capacitor banks. Direct control of the laser Pockels cell drive enables optimal pulse energy extraction, and up to four 2 J laser pulses during one flashlamp pulse. These lasers are used in the Thomson scattering plasma diagnostic system on the MST reversed-field pinch to study the dynamic evolution of the electron temperature.
Citation Martínez‐García EA, Chávez‐Robles B, Sánchez‐Hernández PE, Nuñez‐Atahualpa L, Martín‐Máquez BT, Muñoz‐Gómez A, González‐López L, Gámez‐Nava JI, Salazar‐Páramo M, Dávalos‐Rodríguez I, Petri ...MH, Zuñiga‐Tamayo D, Vargas‐Ramírez R, Vázquez‐Del Mercado M. IL‐17 Increased in the third trimester in healthy women with term labor. Am J Reprod Immunol 2011; 65: 99–103
Introduction The function, peripheral blood expression, and physiologic importance of IL‐17 is not well established. Detection of IL‐17 in sera and plasma samples from patients with pre‐eclampsia has been reported with inconsistent results. To establish the l levels of the IL‐17 at peripheral level, we studied prospectively a cohort of 13 healthy pregnant women.
Objective To evaluate the changes in serum levels of IL‐17 in healthy pregnant women in a prospective cohort.
Material and Methods Thirteen healthy pregnant women were prospectively followed to evaluate serum levels of IL‐17. Each patient was evaluated at each trimester. IL‐17 levels were measured by ELISA. The statistical analysis was done using repeated measures anova and Bonferroni′s multiple comparison test.
Results IL‐17 levels were significantly increased from first trimester with a mean of 14.61 up to 31.78 pg/mL at third trimester (P < 0.05), but when detectable, they were almost identical range in all trimesters.
Conclusions We propose that IL‐17 levels in healthy women are present with very similar range levels during the whole pregnancy but the average is increased during the third trimester maybe as a part of the complex network of cytokines as a result of implantation, fetal development, and labor process itself.
Human polyclonal antibodies (hPABs) are useful therapeutics, but because they are available only from human donors, their supply and application is limited. To address this need, we prepared a human ...artificial chromosome (HAC) vector containing the entire unrearranged sequences of the human immunoglobulin (hIg) heavy-chain (H) and lambda (lambda) light-chain loci. The HAC vector was introduced into bovine primary fetal fibroblasts using a microcell-mediated chromosome transfer (MMCT) approach. Primary selection was carried out, and the cells were used to produce cloned bovine fetuses. Secondary selection was done on the regenerated fetal cell lines, which were then used to produce four healthy transchromosomic (Tc) calves. The HAC was retained at a high rate (78-100% of cells) in calves and the hIg loci underwent rearrangement and expressed diversified transcripts. Human immunoglobulin proteins were detected in the blood of newborn calves. The production of Tc calves is an important step in the development of a system for producing therapeutic hPABs.
Efforts to further elucidate structure−activity relationships (SAR) within our previously disclosed series of β-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV ...(DPP-IV) inhibitors led to the investigation of vinyl substitution at the β-position of α-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker fa/fa rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
We have developed a method, using nuclear transplantation, to produce transgenic embryonic stem (ES)-like cells from fetal bovine fibroblasts. These cells, when reintroduced into preimplantation ...embryos, differentiated into derivatives from the three embryonic germ layers, ectoderm, mesoderm, and endoderm, in 5-month-old animals. Six out of seven (86%) calves born were found to be chimeric for at least one tissue. These experiments demonstrate that somatic cells can be genetically modified and then de-differentiated by nuclear transfer into ES-like cells, opening the possibility of using them in differentiation studies and human cell therapy.
Gene targeting is accomplished using embryonic stem cells in the mouse but has been successful, only using primary somatic cells followed by embryonic cloning, in other species. Gene targeting in ...somatic cells versus embryonic stem cells is a challenge; consequently, there are few reported successes and none include the targeting of transcriptionally silent genes or double targeting to produce homozygotes. Here, we report a sequential gene targeting system for primary fibroblast cells that we used to knock out both alleles of a silent gene, the bovine gene encoding immunoglobulin-mu (IGHM), and produce both heterozygous and homozygous knockout calves. We also carried out sequential knockout targeting of both alleles of a gene that is active in fibroblasts, encoding the bovine prion protein (PRNP), in the same genetic line to produce doubly homozygous knockout fetuses. The sequential gene targeting system we used alleviates the need for germline transmission for complex genetic modifications and should be broadly applicable to gene functional analysis and to biomedical and agricultural applications.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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